Formoterol, (+/−)N-[2-hydroxy-5-[1-hydroxy-2 [[2-(p-methoxyphenyl)-2-propyl]amino]ethyl]phenyl]-formamide, is a highly potent long lasting bronchodilator when inhaled. Formoterol has two chiral centers in the molecule, each of which can exist in two possible configurations. Thus, formoterol has four stereoisomers: (R,R), (S,S), (R,S) and (S,R). The racemic mixture that is commercially available for administration is a dihydrate of the fumarate salt. The order of potency of the isomers is (R,R)>>(R,S)=(S,R)>(S,S), and the (R,R)-isomer is 1000-fold more potent than the (S,S)-isomer. Administration of the pure (R,R)-isomer also offers an improved therapeutic ratio. U.S. Pat. No. 6,268,533 and PCT application WO 00/21487 disclose that the L-(+)-tartrate salt of R,R-formoterol is unexpectedly superior to other salts of R,R-formoterol, being easy to handle, pharmaceutically innocuous and non-hygroscopic. Also, U.S. Pat. No. 6,268,533 and U.S. Pat. No. 6,472,563, which are hereby incorporated by reference herein in their entireties, disclose that the L-tartrate salt of R,R-formoterol exists in three polymorphic forms, polymorph (A), (B), and (C).
Formoterol drug substances are known to be stable at ambient conditions for up to two years. However, when R,R-formoterol L-tartrate salt is mixed with lactose, degradation is known to occur (Maillards reaction) because of interactions between the amino groups within the R,R-formoterol L-tartrate salt molecule and the lactose moiety.
Dry powder inhalation devices usually need to be packed in a substantially impermeable package to prevent atmospheric moisture ingress. The use of such impermeable packages may cause accumulation of certain trace substances within the sealed local environment to a level sufficient for them to interact with the pharmaceutical composition contained in the dry powder inhalation device. Such interaction, for example, may result in an adduct between the pharmaceutical composition and the trace substance, resulting in the formation of degradation products. For instance, a dry powder inhaler generally includes a number of plastic components molded from an acetal homopolymer, and the plastic components may contain trace formaldehyde formed as a breakdown product during the molding of acetal resins. It is believed that the trace formaldehyde released from the plastic components is capable of forming an adduct with various pharmaceutical compositions when packaged within a substantially impermeable container.
Accordingly, what is needed is a stable pharmaceutical product comprising R,R-formoterol L-tartrate salt, and in particular crystalline R,R-formoterol L-tartrate salt, in a dry powder inhalation device, wherein the degradation of R,R-formoterol L-tartrate salt is reduced or eliminated.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.